New arylglycinamide derivatives, processes for the manufacture thereof and pharmaceutical compositions containing these compounds

ABSTRACT

The invention relates to new arylglycinamide derivatives of general formula I  
                 
 
     and the pharmaceutically acceptable salts thereof, wherein  
     R 1  and R 2  together with the N to which they are bound form a ring of the formula  
                 
 
     wherein  
     p is 2 or 3 and  
     X denotes oxygen, N(CH 2 ) n R 6  or CR 7 R 8 ,  
     and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Ar and n have the meanings given in the specification, and the preparation and use thereof. The new compounds are valuable neurokinin (tachykinin)-antagonists.

[0001] The invention relates to new arylglycinamide derivatives ofgeneral formula I

[0002] and the pharmaceutically acceptable salts thereof, processes forpreparing them and pharmaceutical compositions containing thesecompounds. The compounds are valuable neurokinin (tachykinin)antagonists.

[0003] The abbreviations used in the specification and claims areexplained as follows:

[0004] CDI=Carbonyldiimidazole

[0005] DCCI=Dicyclohexylcarbodiimide

[0006] HOBt=1-Hydroxybenzotriazole

[0007] THF=Tetrahydrofuran

[0008] DMF=Dimethylformamide

[0009] RT=Room temperature

[0010] DMAP=4-Dimethylaminopyridine

[0011] TBTU=O-Benzotriazolyl-tetramethyluronium-tetrafluoroborate

[0012] In order to show the formulae, a simplified representation isused. In the representation of the compounds all CH₃-substituents arerepresented by a single bond, and for example the following formula

[0013] The invention relates to new arylglycinamide derivatives ofgeneral formula I

[0014] or the pharmaceutically acceptable salts thereof, wherein

[0015] Ar denotes unsubstituted or mono- to penta-substituted phenyl, orunsubstituted or mono- or di-substituted naphthyl, [in which thesubstituents of the phenyl and naphthyl independently of each otherdenote halogen (F, Cl, Br, I), OH, (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃or NR⁹R¹⁰ (wherein R⁹ and R¹⁰ independently of each other denote H,methyl or acetyl)] or Ar is phenyl substituted by —OCH₂O— or —O(CH₂)₂O—;

[0016] R¹ and R² together with the N to which they are bound form a ringof the formula

[0017] wherein

[0018] p is 2 or 3,

[0019] X denotes oxygen, N(CH₂)_(n)R⁶ or CR⁷R⁸, wherein

[0020] n is 0, 1 or 2,

[0021] R⁶ is (C₃₋₇)cycloalkyl, phenyl or naphthyl, wherein the phenylmay be mono- to tri-substituted by halogen (F, Cl, Br, I), (C₁₋₄)alkyl,O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶ independentlyof each other denote H, methyl or acetyl);

[0022] R⁷ and R⁸ have one of the following meanings:

[0023] a) R⁷ and R⁸ represent H if R³ is unsubstituted or substitutedphenyl,

[0024] b) R⁷ is phenyl, phenyl substituted by 1 to 3 substituents[wherein the substituents independently of one another denote halogen(F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃ or OCF₃], piperidinyl,1-methylpiperidinyl,

[0025]  if R⁸ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, CN

[0026]  or —C(O)N((C₁₋₃)alkyl)₂

[0027] or

[0028] c) R⁷ and R⁸ together form the group

[0029] R³ denotes H, (C₁₋₄) alkyl, unsubstituted or mono- totri-substituted phenyl, wherein the substituents independently of oneanother represent halogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄) alkyl,CF₃, OCF₃ or NR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ independently of one anotherdenote H, methyl or acetyl);

[0030] R⁴ denotes phenyl(C₁₋₄)alkyl or naphthyl (C₁₋₄)alkyl, whereinphenyl may be substituted by 1 to 3 substituents, wherein thesubstituents independently of one another are halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰independently of one another denote H, methyl or acetyl);

[0031] and

[0032] R⁵ denotes H, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, CH₂COOH,—CH₂C(O)NH₂, —OH or phenyl(C₁₋₄)alkyl.

[0033] The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have both substance P-antagonism and alsoneurokinin A- or neurokinin B-antagonistic properties. They are usefulfor the treatment and prevention of neurokinin-mediated diseases.

[0034] Compounds of general formula I may contain acid groups, chieflycarboxyl groups, and/or basic groups such as, for example, aminofunctions. Compounds of general formula I may therefore be obtainedeither as internal salts, as salts with pharmaceutically acceptableinorganic acids such as hydrochloric acid, sulphuric acid, phosphoricacid or sulphonic acid or organic acids (such as, for example, maleicacid, fumaric acid, citric acid, tartaric acid or acetic acid) or assalts with pharmaceutically acceptable bases such as alkali or alkalineearth metal hydroxides or carbonates, zinc or ammonium hydroxides ororganic amines such as, for example, diethylamine, triethylamine ortriethanolamine, etc.

[0035] The compounds according to the invention may occur as racematesbut may also be obtained as pure enantiomers, i.e. in (R)- or (S)-form.They may also occur as diastereoisomers or mixtures thereof.

[0036] The preferred compounds of general formula I are those wherein

[0037] R¹ and R² together with the N to which they are bound form a6-membered ring of the formula

[0038] wherein

[0039] X denotes N(CH₂)_(n)R⁶ or CR⁷R⁸,

[0040] wherein n, R⁶, R⁷ and R⁸ are defined as in claim 1.

[0041] Particular mention should be made of compounds of formula Iwherein

[0042] X is N(CH₂)_(n)R⁶ wherein n is 0, 1 or 2 and R⁶ is(C₃₋₇)cycloalkyl or phenyl, particularly those compounds wherein n is 0and R⁶ is (C₃₋₇)cycloalkyl, particularly those compounds wherein R⁶ iscyclobutyl or cyclohexyl.

[0043] Mention should also be made of compounds of formula I wherein

[0044] R⁷ and R⁸ have one of the following meanings:

[0045] a) R⁷ and R⁸ denote H when R³ is unsubstituted or substitutedphenyl,

[0046] b) R⁷ is phenyl, piperidinyl

[0047]  if R⁸ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃ or CN,

[0048] or

[0049] c) R⁷ and R⁸ together form the group

[0050]  particularly those wherein

[0051] R⁷ and R⁸ have one of the following meanings:

[0052] a) R⁷ and R⁸ denote H when R³ is unsubstituted or substitutedphenyl,

[0053] b) R⁷ is phenyl,

[0054]  when R⁸ is H, —CONH₂ or CN,

[0055] or

[0056] c) R⁷ and R⁸ together form the group

[0057] The preferred compounds are those wherein

[0058] R⁷ denotes phenyl,

[0059] and R⁸ is H or CN, particularly those wherein R⁷ is pyridino andR⁸ is H.

[0060] Of the compounds defined above, the preferred ones are thosewherein

[0061] Ar denotes unsubstituted or mono- or di-substituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br, I), OH, methyl,methoxy, CF₃, OCF₃ or dimethylamine] or Ar is phenyl substituted by—OCH₂O—, this group connecting positions 2 and 3 or 3 and 4 of thephenyl, particularly those wherein

[0062] Ar denotes unsubstituted or mono- or di-substituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br), methoxy or CF₃] orAr is phenyl substituted by —OCH₂O—, this group connecting positions 2and 3 or 3 and 4 of the phenyl.

[0063] The preferred compounds are those wherein Ar is phenyl,3,4-dichlorophenyl, 3,4-dimethoxyphenyl or 3,4-methylenedioxyphenyl.

[0064] Of the compounds defined above, particular mention should be madeof those wherein R³ is phenyl or preferably H.

[0065] Of the compounds defined above, mention should also be made ofthose wherein

[0066] R⁴ denotes phenyl(C₁₋₃)alkyl, wherein phenyl may be substitutedby 1 or 2 substituents, the substituents independently of one anotherbeing halogen (F, Cl, Br, I), methyl, methoxy, CF₃ or OCF₃;

[0067] and

[0068] R⁵ denotes H, (C₁₋₃)alkyl, CH₂COOH, —CH₂C(O)NH₂ or phenethyl,

[0069] particularly those compounds wherein

[0070]  and R⁵ denotes H or CH₃.

[0071] The following compounds are preferred:

[0072] The term naphthyl used above includes both 1-naphthyl and2-naphthyl.

[0073] Test results for compounds according to the invention:

[0074] The receptor affinity for the NK₁-receptor (substance P-receptor)is determined on human lymphoblastoma cells (IM-9) with clonedNK₁-receptors, measuring the displacement of ¹²⁵I-labelled substance P.The K_(i)-values thus obtained demonstrate the efficacy of thecompounds: K_(i) Compound of Example 3: 1.4 nM Compound of Example 4:1.0 nM Compound of Example 5: 1.3 nM Compound of Example 33: 1.3 nMCompound of Example 45: 1.6 nM Compound of Example 46: 1.4 nM Compoundof Example 52: 1.1 nM Compound of Example 53: 2.3 nM Compound of Example58: 6.4 nM Compound of Example 59: 4.2 nM Compound of Example 65: 9.2 nMCompound of Example 66: 1.4 nM Compound of Example 68: 1.5 nM Compoundof Example 70: 2.8 nM Compound of Example 71: 2.1 nM Compound of Example72: 6.8 nM Compound of Example 73: 1.7 nM Compound of Example 74: 11.8nM  Compound of Example 75:  180 nM  Compound of Example 76: 7.0 nM

[0075] The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have, in particular, NK₁-antagonism, butalso NK₂- and NK₃-antagonistic properties.

[0076] The compounds according to the invention are valuable neurokinin(tachykinin) antagonists which have both substance P-antagonism and alsoneurokinin A- or neurokinin B-antagonistic properties. They are usefulfor the treatment and prevention of neurokinin-mediated diseases:treatment and prevention of inflammatory and allergic diseases of therespiratory tract, such as asthma, chronic bronchitis, emphysema,rhinitis or coughs, eye diseases such as conjunctivitis and iritis, skindiseases such as dermatitis in contact eczema, urticaria, psoriasis,sunburn, insect bites and stings, neurodermitis, itching andpostherpetic pain,

[0077] diseases of the gastrointestinal tract such as gastric andduodenal ulcers, ulcerative colitis, Crohn's disease, irritable bowel,Hirschsprung's disease;

[0078] diseases of the joints such as rheumatoid arthritis, reactivearthritis and Reiter syndrome;

[0079] for treating diseases of the central nervous system such asdementia, Alzheimer's disease, schizophrenia, psychosis, depression,headaches (e.g. migraine or tension headaches) and epilepsy;

[0080] for the treatment of tumours, collagenosis, dysfunction of theurinary tract, haemorrhoids, nausea and vomiting, triggered for exampleby radiation or cytostatic therapy or motion and pain of all kinds.

[0081] The invention therefore also relates to the use of the compoundsaccording to the invention as remedies and pharmaceutical preparationswhich contain these compounds. They are preferably for use in humans.The compounds according to the invention may be administered byintravenous, subcutaneous, intramuscular, intraperitoneal or intranasalroute or by inhalation, by transdermal route, if desired with the aid ofiontophoresis or enhancers known from the literature, and by oral route.

[0082] For parenteral administration, the compounds of formula I or thephysiologically acceptable salts thereof, optionally with conventionalsubstances such as solubilisers, emulsifiers or other adjuvants, may bemade into solutions, suspensions or emulsions. Suitable solventsinclude, for example, water, physiological saline solutions or alcohols,e.g. ethanol, propanediol or glycerol, sugar solutions such as glucoseor mannitol solutions or a mixture of various solvents.

[0083] In addition, the compounds may be administered by means ofimplants, e.g. of polylactide, polyglycolide or polyhydroxybutyric acidor by means of intranasal preparations.

[0084] The oral effectiveness of compounds of general formula I can bedemonstrated using the following standard test:

[0085] Inhibition of the lowering of blood pressure caused by NK₁ inanaesthetised guinea pigs.

[0086] Guinea pigs weighing 300-500 grams were anaesthetised withpentobarbital (50 mg/kg i.p.), intubated and mechanically ventilatedwith 10 ml of ambient air per kg of body weight at a rate of 60 breathsper minute. The blood pressure was measured in the blood flow throughthe carotid artery. In order to introduce substances intravenously, thejugular vein was cannulated.

[0087] By the intravenous administration of the NK₁-agonist [βAla⁴,Sar⁹, Met(O₂)¹¹] SP(4-11) (0.2 μmol/kg) a brief lowering of the bloodpressure was triggered which was repeated at 10 minute intervals byrepeatedly giving the NK₁-agonist.

[0088] The neurokinin-antagonist was then administered by intraduodenalroute and at 10 minute intervals a lowering of blood pressure wasinduced by means of the NK₁-agonist.

[0089] The inhibition of the lowering of blood pressure caused by theabove-mentioned NK₁-agonist was measured before and after treatment withthe neurokinin-antagonist.

[0090] The compound of Example 5 yielded an ID₅₀ of 1.4 mg/kg. (ID₅₀ isthe dose which inhibits the lowering of blood pressure caused by theNK₁-agonist by 50%.)

[0091] The compounds according to the invention may be prepared bygenerally known methods.

[0092] The compounds may be prepared in various ways. The two commonestmethods are shown in the following scheme:

[0093] Method A.

[0094] The carboxylic acid may be linked to the amine HN (R⁵) R⁴ invarious ways. The usual methods are coupling methods such as those usedin peptide chemistry. A coupling reagent such as TBTU, DCCI/HOBt, CDI,etc., is added to the coupling partners in an approximately equivalentamount. Suitable solvents are DMF, THF, CH₂Cl₂, CHCl₃, acetonitrile orother inert solvents or mixtures thereof. The appropriate temperaturerange is between −50° C. and +120° C., preferably between 0° C. and 40°C.

[0095] The carboxylic acid may also initially be converted by means ofSOCl₂, SO₂Cl₂, PCl₃, PCl₅ or PBr₃ or mixtures thereof, by known methods,into the corresponding acid halide which is subsequently reacted withthe amine HN(R⁵)R⁴ in an inert solvent such as CH₂Cl₂, THF or dioxane attemperatures between −50° C. and +100° C., typically between 0° C. and20° C.

[0096] Another alternative is to convert the carboxylic acid initiallyinto the alkylester, usually the methylester, by known methods and thento react this ester with the amine HN(R⁵)R⁴ in an inert solvent such asDMF, dioxane or THF. The reaction temperatures are between 20° C. and150° C., typically between 50° C. and 120° C. The reaction may also becarried out in a pressurised container.

[0097] Process B.

[0098] In this, the α-halo-arylacetamide derivative obtained accordingto known procedures is reacted with the amine R¹(R²)NH, therebygenerating hydrogen halide. In order to mop up the cleaved (or excess)hydrogen halide, inorganic bases are used such as K₂CO₃, NaHCO₃ orCaCO₃, or organic bases may be used such as triethylamine, Hünig base,pyridine or DMAP, or an excess of the amine R¹(R²)NH may be used. DMF,THF, dioxane or other inert solvents are used. The temperature range forthe reaction is from 0 to 100° C., typically from 10 to 80° C.

[0099] Process C.

[0100] The compounds according to the invention in which R⁵ is not H mayalso be prepared as follows: first of all, the corresponding compound inwhich R⁵ is H is synthesised according to process A or B. ThenN-alkylation is carried out as follows in order to introduce alkyl,cycloalkyl or CH₂COOH. The compound according to the invention whereinR⁵ is H is deprotonated with an equivalent quantity of NaH, NaNH₂, KOH,NaOCH₃ or some other strong base. Anhydrous inert solvents such as THF,dioxane or diethylether are used. Then the corresponding alkylatingagent is added slowly in the form of the corresponding halide, tosylateor mesylate. The reaction is carried out in the temperature range from−50° C. to +100° C., typically between 0° C. and +50° C. The method isdescribed in detail in Example 33.

EXAMPLE 1

[0101]

[0102] 1st Step:

[0103] 2.2 g of 1-cyclohexylpiperazine were dissolved in 150 ml ofanhydrous DMF, mixed with 2 g of K₂CO₃, stirred at room temperature for20 minutes and then cooled to 5° C. 2.7 g of methyl(R,S)-α-bromophenylacetic acid were added and the suspension was stirredovernight at RT. The precipitate was filtered off and the filtrate wasevaporated down. The residue was taken up in ethyl acetate, extractedtwice with 10% KHCO₃ solution and once with saturated NaCl solution. Theorganic phase was dried over Na₂SO₄, filtered and evaporated down, and3.7 g of (R,S)-1-cyclohexyl-4-(methyl 2-phenylacetate)-piperazine wereobtained in the form of a yellow oil.

[0104] Yield: about 100%.

[0105] 2nd Step:

[0106] 2.3 g of the product of the first step were dissolved in 10 ml ofmethanol, mixed with 14 ml of 1N NaOH and the resulting emulsion wasstirred overnight at room temperature. The clear reaction solution wasneutralised by the addition of 14 ml of 1N HCl, evaporated to dryness,the residue was treated with isopropanol and the solid matter wascollected by suction filtration. The filtrate was evaporated down andthe residue was triturated again with isopropanol, the solid matter wassuction filtered and combined with the solid obtained earlier. In thisway, 1.6 g of (R,S)-1-cyclohexyl-4-(2-phenylacetic acid)-piperazine wereobtained as a white solid.

[0107] Yield: 75%.

[0108] 3rd Step:

[0109] 0.6 g of the product of the second step, 0.48 g of3,5-bis-(trifluoromethyl)-benzylamine and 0.32 g of HOBT were suspendedin 60 ml of THF/CH₂Cl₂ (1:1) and adjusted to pH 8.5 by the addition ofabout 0.7 ml of Hünig base. 0.77 g of TBTU were added and the mixturewas stirred overnight at room-temperature. The clear reaction solutionwas evaporated down in vacuo, the residue was taken up in CH₂Cl₂ andextracted twice with 10% KHSO₄ solution, once with saturated NaClsolution, twice with 10% KHCO₃ solution and once more with saturatedNaCl solution. The organic phase was dried over Na₂SO₄, filtered andevaporated down, whereupon crystallisation took place. 0.685 g of(R,S)-1-cyclohexyl-piperazinyl-4-[2-phenylaceticacid-N-(3,5-bis-trifluoromethylbenzyl)amide] were obtained as ayellowish solid. Yield 64%.

[0110] Mp: 124-129° C. FAB-MS: (M+H)⁺=528.2.

EXAMPLE 2

[0111]

[0112] 1st Step:

[0113] 0.49 g of 3,5-bis-(trifluoromethyl)-benzylamine were dissolved in30 ml of anhydrous CH₂Cl₂, 0.3 ml of triethylamine were added, themixture was cooled in an ice bath and over 20 minutes a solution of 0.46g of (R,S)-α-bromophenylacetyl chloride in 10 ml of CH₂Cl₂ was addeddropwise. After the mixture had stood at room temperature over aweekend, the solvent was eliminated and the solid residue was trituratedwith diethylether, suction filtered and the filtrate was evaporateddown. 0.6 g of α-bromophenylacetic acidN-(bis-trifluoromethyl-benzyl)-amide were obtained as a light beigesolid.

[0114] Yield: 43.5%.

[0115] 2nd Step:

[0116] 0.21 g of 4-propionylamino-piperidine hydrochloride weredissolved in 30 ml of anhydrous DMF, 0.33 g of K₂CO₃ were added and themixture was stirred for 30 minutes at room temperature. Over 20 minutesa solution of 0.68 g of the product of the first step in 10 ml of DMFwere added dropwise to this mixture, which was then stirred overnight atroom temperature. The suspension was filtered, the filtrate wasevaporated down, the oily residue obtained was taken up in ethylacetate, extracted twice with 10% KHCO₃ solution and once with saturatedNaCl solution. The organic phase was dried over Na₂SO₄, filtered, thefiltrate was evaporated down and the semi-solid residue obtained wastriturated with diethylether and suction filtered. 0.33 g of(R,S)-4-propionylamino-1-[2-phenylaceticacid-N(3,5-bis-trifluoromethyl-benzyl)-amide]-piperidine were obtainedas a white solid.

[0117] Yield: 64%. Mp: 189-191° C.

[0118] FAB-MS: (M+H)⁺=516.4.

EXAMPLE 33

[0119]

[0120] Mp: >240° C.; FAB-MS: (M+H)⁺=556.4

[0121] 0.3 g of the compound according to Example 25 were converted intothe corresponding base by treatment with KHCO₃ and dried. The resultingproduct was dissolved in 5 ml of anhydrous THF, 34 mg of NaH (60% inoil) were added and the mixture was stirred for 1.5 hours at roomtemperature. Then 0.1 g of methyliodide were added and the mixture wasstirred overnight. The reaction mixture was mixed with 2 ml of THF/water(1:1) then with 25 ml of water and extracted 3 times with ether. Thecombined ether extracts were dried over Na₂SO₄ and evaporated down invacuo, thereby obtained 170 mg of the desired compound in the form of afree base (oil). This was converted into the dihydrochloride by theaddition of an excess of ethereal HCl, the dihydrochloride beingobtained in the form of yellow crystals.

[0122] Yield: 113 mg (36%).

[0123] The other compounds of the invention may be prepared analogously,e.g. as follows:

EXAMPLE 3

[0124]

[0125] Mp: 235-238° C. FAB-MS: (M+H)⁺=542.2.

EXAMPLE 4

[0126]

[0127] Mp: >240° C. (Decomp.). FAB-MS: (M+H)⁺=542.3.

EXAMPLE 5

[0128]

[0129] Mp: 158-164° C.; FAB-MS: (M+H)⁺=556.4.

EXAMPLE 6

[0130]

[0131] Mp: 97-99° C.; FAB-MS: (M+H)⁺=556.3.

EXAMPLE 7

[0132]

[0133] Mp: >240° (Decomp.); FAB-MS: (M+H)⁺=528.4.

EXAMPLE 8

[0134]

[0135] Mp: 102105° C.; FAB-MS: (M+H)⁺=640.3.

EXAMPLE 9

[0136]

[0137] Mp: 141-149° C.; FAB-MS: (M+H)⁺=579.2.

EXAMPLE 10

[0138]

[0139] Mp: 218-223° C.; FAB-MS: (M+H)⁺=579.3.

EXAMPLE 11

[0140]

[0141] Mp: >220° (Decomp.); FAB-MS (M+H)⁺=571.3

EXAMPLE 12

[0142]

[0143] Mp: 205-210° C.; FAB-MS: (M+H)⁺=591.3.

EXAMPLE 13

[0144]

[0145] Mp: 87-95° C.; FAB-MS: (M+H)⁺=571.2

EXAMPLE 14

[0146]

[0147] Mp: 164166° C.; FAB-MS: (M+H)⁺=537.3.

EXAMPLE 15

[0148]

[0149] Mp: 208-210° C.; FAB-MS: (M+H)⁺=578.3.

EXAMPLE 16

[0150]

EXAMPLE 17

[0151]

EXAMPLE 18

[0152]

EXAMPLE 19

[0153]

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EXAMPLE 78

[0212]

Injectable solution 200 mg of active substance*  1.2 mg of monopotassiumdihydrogen phospate = KH₂PO₄ )  0.2 mg of disodium hydrogen phosphate =) (buffer) NaH₂PO₄.2H₂O )  94 mg of sodium chloride ) or ) (isotonic)520 mg of glucose )  4 mg of albumin (protease protection) q.s.     sodium hydroxide solution ) q.s.      hydrochloric acid ) to adjustthe pH to pH 6 sufficient water to make a 10 ml solution for injectionInjectable solution 200 mg of active substance*  94 mg of sodiumchloride or 520 mg of glucose  4 mg      of albumin q.s.      sodiumhydroxide solution ) q.s.      hydrochloric acid ) to adjust the pH topH 9 sufficient water to make a 10 ml solution for injectionsLyophilisate 200 mg of active substance* 520 mg of mannitol(isotonic/structural component)  4 mg of albumin Solvent 1 forlyophilisate  10 ml of water for injections Solvent 2 for lyophilisate 20 mg of Polysorbate ®80 = Tween ®80 (surfactant  10 ml of water forinjections

1. Arylglycinamide derivatives of general formula I

or the pharmaceutically acceptable salts thereof, wherein Ar denotesunsubstituted or mono- to penta-substituted phenyl, or unsubstituted ormono- or di-substituted naphthyl, [in which the substituents of thephenyl and naphthyl independently of each other denote halogen (F, Cl,Br, I), OH, (C₁₋₄) alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR⁹R¹⁰ (wherein R⁹and R¹⁰ independently of each other denote H, methyl or acetyl)] or Aris phenyl substituted by —OCH₂O— or —O(CH₂)₂O—; R¹ and R² together withthe N to which they are bound form a ring of the formula

 wherein p is 2 or 3, X denotes oxygen, N(CH₂)_(n)R⁶ or CR⁷R⁸, wherein nis 0, 1 or 2, R⁶ is (C₃₋₇)cycloalkyl, phenyl or naphthyl, wherein thephenyl may be mono- to tri-substituted by halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O-(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶independently of each other denote H, methyl or acetyl); R⁷ and R⁸ haveone of the following meanings: a) R⁷ and R⁸ represent H if R³ isunsubstituted or substituted phenyl, b) R⁷ is phenyl, phenyl substitutedby 1 to 3 substituents [wherein the substituents independently of oneanother denote halogen (F, Cl, Br, I), (C₁₋₄) alkyl, O—(C₁₋₄) alkyl, CF₃or OCF₃], piperidinyl, 1-methylpiperidinyl,

 if R⁸ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, CN

 or —C(O)N((C₁₋₃)alkyl)₂ or c) R⁷ and R⁸ together form the group

R³ denotes H, (C₁₋₄)alkyl, unsubstituted or mono- to tri-substitutedphenyl, wherein the substituents independently of one another representhalogen (F, Cl, Br, I), (C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁷R¹⁸(wherein R¹⁷ and R¹⁸ independently of one another denote H, methyl oracetyl); R⁴ denotes phenyl(C₁₋₄)alkyl or naphthyl(C₁₋₄)alkyl, whereinphenyl may be substituted by 1 to 3 substituents, wherein thesubstituents independently of one another are halogen (F, Cl, Br, I),(C₁₋₄)alkyl, O—(C₁₋₄)alkyl, CF₃, OCF₃ or NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰independently of one another denote H, methyl or acetyl); and R⁵ denotesH, (C₁₋₄)alkyl, (C₃₋₆)cycloalkyl, CH₂COOH, —CH₂C(O)NH₂, —OH orphenyl(C₁₋₄)alkyl.
 2. Compounds according to claim 1, wherein R¹ and R²together with the N to which they are bound form a 6-membered ring offormula

wherein X denotes N(CH₂)_(n)R⁶ or CR⁷R⁸, wherein n, R⁶, R⁷ and R⁸ aredefined as in claim
 1. 3. Compounds according to claim 2, wherein X isN(CH₂)_(n)R⁶, wherein n is 0, 1 or 2 and R⁶ is (C₃₋₇)cycloalkyl orphenyl.
 4. Compounds according to claim 3, wherein n is O and R⁶ is(C₃₋₇) cycloalkyl.
 5. Compounds according to claim 4, wherein R⁶ iscyclobutyl or cyclohexyl.
 6. Compounds according to claim 2, wherein Xis CR⁷R⁸, wherein R⁷ and R⁸ have one of the following meanings: a) R⁷and R⁸ denote H when R³ is unsubstituted or substituted phenyl, b) R⁷ isphenyl, piperidinyl

 if R⁸ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃ or CN or c) R⁷ and R⁸together form the group


7. Compounds according to claim 6, wherein R⁷ and R⁸ have one of thefollowing meanings: a) R⁷ and R⁸ denote H when R³ is unsubstituted orsubstituted phenyl, b) R⁷ is phenyl,

 when R⁸ is H, —CONH₂ or CN, or c) R⁷ and R⁸ together form the group


8. Compounds according to claim 7, wherein R⁷ is phenyl,

and R⁸ is H or CN.
 9. Compounds according to claim 8, wherein R⁷ ispyridino and R⁸ is H.
 10. Compounds according to one of claims 1 to 9,wherein Ar denotes unsubstituted or mono- or di-substituted phenyl, orunsubstituted naphthyl [wherein the substituents of the phenylindependently of one another are halogen (F, Cl, Br, I), OH, methyl,methoxy, CF₃, OCF₃ or dimethylamine] or Ar is phenyl substituted by—OCH₂O—, this group connecting positions 2 and 3 or 3 and 4 of thephenyl.
 11. Compounds according to claim 10, wherein Ar denotesunsubstituted or mono- or di-substituted phenyl, or unsubstitutednaphthyl [wherein the substituents of the phenyl independently of oneanother are halogen (F, Cl, Br), methoxy or CF₃] or Ar is phenylsubstituted by —OCH₂O—, this group connecting positions 2 and 3 or 3 and4 of the phenyl.
 12. Compounds according to claim 11, wherein Ar isphenyl, 3,4-dichlorophenyl, 3,4-dimethoxyphenyl or3,4-methylenedioxyphenyl.
 13. Compounds according to one of claims 1 to12, wherein R³ is H.
 14. Compounds according to one of claims 1 to 12,wherein R³ is phenyl.
 15. Compounds according to one of claims 1 to 14,wherein R⁴ denotes phenyl(C₁₋₃)alkyl, wherein phenyl may be substitutedby 1 or 2 substituents, the substituents independently of one anotherbeing halogen (F, Cl, Br, I), methyl, methoxy, CF₃ or OCF₃; and R⁵denotes H, (C₁₋₃)alkyl, CH₂COOH, —CH₂C(O)NH₂ or phenethyl.
 16. Compoundsaccording to claim 15, wherein R⁴ is

and R⁵ is H or CH₃.
 17. Compounds according to claim 1 which are


18. Process for preparing a compound of general formula I according toone of claims 1 to 17, characterised in that a) an acid

 or a halide or alkylester thereof is reacted with an amine

b) an α-haloarylacetamide

 is reacted with an amine

c) a compound I wherein R⁵ is H is N-alkylated; and a compound thusobtained is isolated as a free compound or as a pharmaceuticallyacceptable salt thereof.
 19. Pharmaceutical preparation containing acompound according to one of claims 1 to
 17. 20. Use of a compoundaccording to one of claims 1 to 17 for preparing a pharmaceuticalpreparation for the treatment and prevention of neurokinin-mediateddiseases.
 21. Use of a compound according to one of claims 1 to 17 forthe treatment and prevention of neurokinin-mediated diseases.